Neuronal expression of CD22: Novel mechanism for inhibiting microglial proinflammatory cytokine production

Abstract

Although considered an immunologically privileged site, the central nervous system (CNS) can display significant inflammatory responses, which may play a pathogenic role in a number of neurological diseases. Microglia appear to be particularly important for initiating and sustaining CNS inflammation. These cells exist in a quiescent form in the normal CNS, but acquire macrophage-like properties (including active phagocytosis, upregulation of proteins necessary for antigen presentation, and production of proinflammatory cytokines) after stimulation with inflammatory substances such as lipopolysaccharide (LPS). Recent studies have focused on elucidating the role of neurons in the regulation of microglial inflammatory responses. In the present study, we demonstrate, using neuron-microglial cocultures, that neurons are capable of inhibiting LPS-induced tumor necrosis factor-alpha (TNF-alpha) production by microglia. This inhibition appears to be dependent on secretion of substances at axon terminals, as treatment with the presynaptic calcium channel blocker omega-conotoxin abolishes this inhibitory effect. Moreover, we show that conditioned medium from neuronal cultures similarly inhibits microglial TNF-alpha production, which provides additional evidence that neurons secrete inhibitory substances. We previously demonstrated that the transmembrane protein-tyrosine phosphatase CD45 plays an important role in negatively regulating microglial activation. The recent characterization of CD22 as an endogenous ligand of this receptor led us to investigate whether neurons express this protein. Indeed, we were able to demonstrate CD22 mRNA and protein expression in cultured neurons and mouse brain, using reverse transcriptase-polymerase chain reaction and antibody-based techniques. Furthermore, we show that neurons secrete CD22, which functions as an inhibitor of microglial proinflammatory cytokine production.

Inflammation in Alzheimer’s Disease and Molecular Genetics: Recent Update

“…On the other hand, it has been noted that neurons are able to generate various molecules that are demonstrated to suppress inflammation, such as TREM2, CD22, CD200, CD59 and fractalkine (Hsieh et al 2009;Mott et al 2004;Ransohoff 2007;Singhrao et al 1999;Walker et al 2009). Interestingly, several of these molecules have been found to be deficient in AD.…”

The cellular response in neuroinflammation: The role of leukocytes, microglia and astrocytes in neuronal death and survival

“…CD45 is also an inhibitory receptor for CD22, a molecule expressed by B cells and CNS neurons [38]! The higher levels of CD45 expressed by peripheral immune cells suggests that neurons have a greater potential to inhibit acutely infiltrating macrophages than CNS resident microglia!…”

Reduction of Amyloid Angiopathy and Aβ Plaque Burden after Enriched Housing in TgCRND8 Mice

“…Remarkably, genes products that are involved in the proinflammatory response such as chemokine [C-C motif] ligand 2 (Ccl2 or MCP-1) 24 or prostaglandin E receptor 2 (EP2 or Ptger2) 25 were down-regulated, whereas anti-inflammatory associated genes such as Cd22 26 or protein tyrosine phosphatase, nonreceptor type 2 (Ptpn2) 27 were up-regulated in brains of EH mice. Inflammation processes in AD brains lead to both enhanced cytotoxicity as well as enhanced A␤ aggregation.…”